Transneuronal Propagation of Pathologic ?-Synuclein from the Gut to the Brain Models Parkinson?s disease. Sangjune Kim1,2, Seung-Hwan Kwon1,2, Seung Pil Yun1,2, Tae-In Kam1,2, Nikhil Panicker1,2, Senthilkumar S. Karuppagounder1,2, Saebom Lee1,2, Jun Hee Lee1,2,10, Wonjoong Richard Kim1,2, Minjee Kook1,2, Catherine A. Foss3, Chentian Shen3,11, Subhash Kulkarni4, Pankaj J. Pasricha4, Gabsang Lee1,2,5, Martin G. Pomper3, Valina L. Dawson1,2,5,6,8, Ted M. Dawson1,2,5,7,8,9,#, and Han Seok Ko1,2,8,9,# 1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, 2Department of Neurology, 3The Russell H. Morgan Department of Radiology and Radiological Science, 4Center for Neurogastroenterology, Department of Medicine, 5Solomon H. Snyder Department of Neuroscience, 6Department of Physiology, 7Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 8Adrienne Helis Malvin Medical Research Foundation, 9Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA Present Address: 10Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA 11Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People?s Hospital, Shanghai 200233, China #Correspondence: tdawson@jhmi.edu (T.M.D.), hko3@jhmi.edu (H.S.K.) Analysis of human pathology led to the Braak hypothesis that ?-synuclein (?-syn) pathology spreads from gut to brain, via the vagus nerve. Here, we test Braak?s hypothesis by assessing ?-synucleinopathy in the brain in a novel gut-to-brain ?-syn transmission mouse model, where pathological ?-syn preformed fibrils (PFF) were injected into the duodenal and pyloric muscularis layer. Spread of pathologic ?-syn in brain, as assessed by phosphorylation of serine 129 of ?-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons, motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and ?-syn deficiency prevented the gut-to-brain spread of ?- synucleinopathy and associated neurodegeneration and behavioral deficits. This study implicates the Braak hypothesis in the etiology of idiopathic PD.